Impact of Circulating Tumor DNA and Copy-Number Alterations on Clinical Outcome in Relapsed/Refractory Germ Cell Tumors Treated With Salvage High-Dose Chemotherapy
Abstract
PURPOSE High-dose chemotherapy (HDCT) is one of the salvage therapy options for patients with relapsed/refractory germ cell tumors (rGCT) after failure of first-line chemotherapy. We aimed to identify circulating biomarkers predicting clinical response and outcome of HDCT. METHODS Baseline and on-treatment plasma samples from 69 HDCT-treated and 26 conventional-dose chemotherapy (CDCT)-treated GCT patients were analyzed by shallow whole-genome sequencing. Tumor fraction (TF) and copy-number alterations (CNAs) were determined using ichorCNA, compared with miR-371a-3p levels, and correlated with progression-free survival (PFS) and overall survival (OS). CNA profiles from external tissue GCT cohorts were used for validation. RESULTS TF was detectable in 75.4% of baseline plasma of HDCT patients. High TF was strongly associated with worse OS in HDCT-treated nonseminomas ( P = .021). This was confirmed in the CDCT cohort ( P = .039), where shorter median OS was observed in high-TF patients compared with the HDCT cohort. Conversely, miR-371a-3p levels were not prognostic. Plasma CNA profiling confirmed the high frequency of chromosome 3p gain in rGCT cases and revealed other alterations linked to poor HDCT outcomes, including 9q and 11q gains and 6q loss. These CNAs were enriched in a cluster predominantly composed of GCT with extra-embryonic histology (yolk sac and choriocarcinoma). Unsupervised clustering of CNA profile of plasma identified 13 patients in this high-risk cluster, who had significantly worse PFS and OS compared with other rGCT cases. CONCLUSION Analysis of cell free DNA provides valuable prognostic information in rGCTs. High baseline TF and specific CNA patterns linked to extra-embryonic histology identify patients at higher risk of poor outcomes. HDCT seems to be more effective than CDCT in high-TF patients. These minimally invasive biomarkers could refine risk stratification and guide selection of salvage therapies in rGCTs.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (18)
Milena Urbini
Thomas F. Eleveld
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Maurizio Polano
Emanuela Scarpi
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Cecilia Menna
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Caterina Gianni
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Ferdinand W. Janssen
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Giuseppe Schepisi
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Giorgia Gurioli
Lucia Kucerova
Ad J.M. Gillis
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Alessandra Virga
Sara Bleve
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Giovanni Rosti
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Paola Ulivi
Michal Mego
Leendert H.J. Looijenga
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Ugo De Giorgi
Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy